High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models

Cell. 2020 Oct 15;183(2):429-441.e16. doi: 10.1016/j.cell.2020.09.007. Epub 2020 Sep 4.

Abstract

Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody VH domain library from which we identified a high-affinity VH binder ab8. Bivalent VH, VH-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. VH-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of VH-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.

Keywords: SARS-CoV-2; electron microscopy; human V(H) antibody domain; mouse and hamster models; virus neutralization.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / ultrastructure
  • Antibodies, Viral / administration & dosage
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology
  • Antibodies, Viral / ultrastructure
  • Antibody Affinity
  • COVID-19
  • Coronavirus Infections / drug therapy*
  • Cricetinae
  • Female
  • Humans
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin Heavy Chains / administration & dosage*
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / immunology
  • Immunoglobulin Heavy Chains / ultrastructure
  • Immunoglobulin Variable Region / administration & dosage*
  • Immunoglobulin Variable Region / chemistry
  • Immunoglobulin Variable Region / immunology
  • Immunoglobulin Variable Region / ultrastructure
  • Mice
  • Mice, Inbred BALB C
  • Mutation
  • Pandemics
  • Peptide Library*
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / drug therapy*
  • Protein Domains
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Spike Glycoprotein, Coronavirus / ultrastructure

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin Fc Fragments
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Peptide Library
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • COVID-19 drug treatment